Tetramethylpyrazine (TMP, also called Chuxiongqin) is a type of alkaloids extracted from herb Ligusticum wallichii (Chuanxiong) of traditional Chinese medicine, and has been used for the treatment of coronary heart disease, angina and ischemic cerebrovascular disease (including cerebral thrombosis and cerebral embolism). TMP has certain pharmacological activities. TMP has significant anticoagulant effects. TMP can significantly inhibit the expression of LPS-induced PAI-1 protein and its mRNA in endothelial cells (Song, et al., Chinese Medical J. 113:136, 2000). TMP, in a low-dose, can inhibit the decomposition of phosphatidylinositol and the formation of TXA2, while in a high dose, can inhibit platelet aggregation through combination of glycoprotein IIb/IIIa (Sheu, et al., Thromb Res. 88:259, 1997). TMP has direct thrombolytic effect. Both artery and venous thrombosis models in rats indicate that TMP has anti-thrombolytic effect (Liu and Sylvester, Thromb Res. 58:129, 1990), which may be related to TMP's inhibition on platelet activity, including inhibition of intracellular Ca2+ activity, inhibition of phosphate diesterase activity, increase of intracellular cAMP level, and reduction of exposure of glycoprotein IIb/IIIa on the platelet surface (Liu and Sylvester, Thromb Res. 75:51, 1994).
More importantly, TMP has significant effect on protecting nerve cells. TMP may significantly alleviate the MCAo-induced ischemia in rat brain cells, and may significantly remove free radicals produced by human neutrophils. TMP may also protect nerve cells through regulation on the expression of Bcl-2 and Bax to reduce apoptosis (Hsiao, et al. Planta Med. 2006, 72:411-417; Kao, et al. Neurochem Int. 2006, 48:166). TMP is also a calcium channel blocker, and at the same time can facilitate the potassium channel opening. TMP has the effects of inhibiting calcium influx, inhibiting the formation of free radicals, enhancing the activity of superoxide dismutase (SOD), inhibiting lipid peroxidation, and inhibiting inflammatory responses (Zhu, et al., Eur. J. Pharmacol. 510:187, 2005).
Tanshinol (Danshensu) is one of major active ingredients of traditional Chinese medicine salvia miltiorrhiza, and can be used for treating cardiovascular diseases with functions of improving heart function and coronary circulation, anticoagulation, and improving microcirculation, and also has effects of such as anti-inflammation, anti-tumor, resisting cerebral thrombosis, and protecting liver. With an o-diphenol hydroxyl and o-hydroxy-carboxylic acid structure, Danshensu is extremely easy to be oxidized and deteriorated, and thus is hard to be stored. The polar groups of Danshensu may be bonded to such as glucuronic acid and be excreted with the urine. The in vitro half-life of Danshensu is very short, bioavailability is only 9.53-14.18%, such that repetitive administrations may be necessary and the clinical application is limited (Wang Tingfang, Journal of Pharmaceutical Practice, 29 (2): 83-87, 2011).
Caffeic acid, as a polyhydroxy styrene acid compound, is widely found in some botanical food such as tomatoes, carrots, strawberry, blueberry and cereals, and Chinese herbal medicines. Caffeic acid has various pharmacological effects of such as anti-inflammation, antibacterial, and improving white blood cell and bold plate, and thus can be used for preventing and treating various diseases associated with oxidative stress, inflammatory reaction and viral infection, such as cardiovascular diseases, brain tissue damage, human immunodeficiency virus (HIV) infection, and leucopenia and thrombocytopenia (Prasad N R, et al. J Photochem Photobiol B, 2009, 95 (3): 196-203). Although having good pharmacological effects, caffeic acid is also very prone to oxidative deterioration, and is difficult to store. Caffeic acid has a structure containing phenolic hydroxyl groups and carboxyl groups and thus can be excreted with urine in the form of glucuronic acid and sulfuric acid conjugates and the like (Gumbinger H G, et al. Planta Med, 1993, 59 (6): 491-493), such that the in vivo half-life is also very short and repeatitive drug administration would be required, which limits its clinical applications.
Oxidative stress refers to the body when subjected to a variety of harmful stimuli, the oxidation system and anti-oxidation system becomes imbalance, the degree of oxidation exceeds the oxide scavenging capacity, resulting in tissue damage. Oxidative stress plays a very important role in the pathogenesis of many diseases and aging. The accumulation of reactive oxygen species can cause nucleic acid cleavage, enzymatic inactivation, polysaccharide depolymerization, lipid peroxidation, eventually leading to tissue damage and even death (Yan et al. Free Radic Biol Med. 2013, 62:90-101). Because oxidative stress causes the body to be in a vulnerable state, it also enhances the virulence of the causative agent and can lead to gene mutations (Beck M A. Proe Nutr Soe. 1999, 58 (3): 707-711). It is currently believed that oxidative stress is closely related to various neurodegenerative diseases including Parkinson's disease (PD) and Alzheimer's disease (AD).
The most common cardiovascular and cerebrovascular diseases generally include coronary heart disease and stroke. Suc diseases are due to arterial stenosis, and caused by insufficient blood supply. The arterial intimal damage, lipid deposition, and platelet and fibrin deposition on lipid plaque may result in thickening of the vessel wall, narrowing of the vascular lumen, and leading to arterial wall atherosclerosis. Sclerosis plaque thrombosis may cause blockage of blood vessels, triggering ischemic heart disease or ischemic cerebrovascular diseases. If blood flow is not restored within 20-40 minutes, it can cause irreversible death of cardiomyocytes or brain cells. During ischemia, a portion of electrons detach from the oxidized respiratory chain of mitochondria and transfer oxygen molecules to form superoxide anions (O2.−). The superoxide anions are very active and can be further subjected to enzymatic catalytic or metal catalytic reactions with other molecules to form secondary ROS, including free radicals of .OH, ROO., H2O2 and ONOO− (Miller et al. Free Radic. Biol. 8:95-108.; Valko et al. Curr. Med. Chem. 2005, 12:1161-1208). These free radicals can destabilize biofilms such as mitochondrial membranes and cell membranes, causing protein denaturation, DNA damage and apoptosis (Siems et al. Life Sci. 1995, 57: 785-789; Stadtman. Curr. Med. Chem. 2004, 11:1105-1112).
Neurodegenerative diseases are related to a progressive condition of irreversible loss of neurons in brain or spinal cord. The irreversible loss of neurons or their myelin sheaths may cause functional disorder. Common neurodegenerative diseases include cerebral ischemia, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and the like. The pathogenesis of neurodegenerative diseases is extremely complex. The neuronal damage is related to many factors such as oxidative stress, calcium overload, inflammatory reaction and apoptosis.